5-hydroxy-{60 (substituted aminomethyl)-mu-xylene-{60 ,{60 -diols

ABSTRACT

Compounds of the formula:   ARE DISCLOSED, WHEREIN R1 and R2 are hydrogen; or where R1 is methyl, R2 is hydrogen, phenyl, or phenyl substituted in the para-position by hydroxy, alkoxy, chloro, phenyl or alkyl having 1-6 carbon atoms. The compounds of this invention are useful in the treatment of bronchial asthma. These compounds exhibit unique biological properties in that they provide the desired bronchial dilation effect without accompanying cardiac stimulation.

United States Patent Schwender et al.

[ 1 5-HYDROXY-a(SUBSTlTUTED AMINOMETHYL)-MU-XYLENE-a,a-DIOLS [75]Inventors: Charles F. Schwender, Lebanon;

John Shavel, Jr., Mendham, both of NJ.

[73] Assignees Warner-Lambert Company, Morris Plains, NJ.

[22 Filed: Dec. 26, 1973 211 App]. No.: 428,557

Related US. Application Data [62] Division of Ser. No. 275,6l 1, July27, I972.

[52] US. Cl 260/471 R; 260/519; 260/570.6;

424/309; 424/319; 424/330 [5]] Int. Cl. C070 101/42 [58] Field of Search260/471 R, 519, 570.6

[56] References Cited UNITED STATES PATENTS 3,686,271 8/l972 Lefon260/47l R Primary E.\-aminerLorraine A. Weinberger Assistant Examiner-L.A. Thaxton Attorney, Agent, or FirmAlbert H. Graddis; Frank S.

Chow

[ Apr. 22, 1975 57 ABSTRACT Compounds of the formula:

9 HOHCHZNHQ cu, R t

no cu 1cu 5 Claims, No Drawings 1 S-HYDROXY- a (SUBSTITUTEDAMINOMETHYL)-MU-XYLENE-a,a-DIOLS This is a division, of application Ser.No. 275,611

Referring now to the above reaction scheme, the synthesis of thecompounds of the invention:

on filed July 27, 1972. C 6 3 The present invention relates to novelcompounds. 5 More particularly, the present invention relates to com- R1pounds having the following structural formula:

CH3 no -on,0n ouoncumnd-cm-M I 1' l involve the formation of the monomethyl ester of S-benzyloxyisophthalate (II). The intermediate H0 cmonbenzyloxy-3-carboxy-a-(methylsulfinyl)-acetophenone (Ill) is obtained bytreatment of II with dimethylsulfinyl wherem 1 and 2 are y g 1 1Smethyl, anion. Aqueous acetic acid treatment of III causes a 2 ishydrogen P y Substituted the P Pummerer rearrangement of III and to givethe methyl Position y y y alkoxy, 'p y or y thiomethyl acetal (IV) andsubsequent hydrolysis to having carbon atoms branched or Stfalghtchalnthe corresponding substituted phenylglyoxal product Among thePreferred Species those Compounds V. Reductive amination of IV or V withthe appropriate wherein R1 and 2 are hydrogen; 2 15 y Pg and 1 amine andKBI-L, gives 3-benzyloxy-5-[2-(substituted i5 y and Where 1 is methyland 2 15 p y amino)1-(hydroxy)ethyl]-benzoic acid, VI. Esterifi- I ddesters of the above compounds h s cation of VI with methanol andethanesulfonic acid acetate, prop ate, benzoate, succinate, as ll asgives the ester VII, which is reduced with LiAlH, to azolidinederivatives, are also features of this invention. iv VIII, C l ireduction d b l VIII d The compounds of this invention also form saltswith ives the desired product, IX. pharmaceutically acceptable acids orbases and these Th compound 1X i l th i d f di h l salts are alsoincluded within the scope of this inven- 5 h d i h h l (X) b reaction ih di h tion. sulfinyl anion giving the intermediate methyl 5- Accordingto the present invention, the above comsh d 3[ th 1 ]fi 1)acetyubenzoate (XI), pounds are prepared by reactions which areillustrated A id- 1 d pummel-er rearrangement f X] by the followingreaction scheme: gives the corresponding methylthiomethyl acetal (XII)(mocha (B sos Hno C O O CH: H5O nCHzO- C O 0 CH1 0 0 0 /SCH3 1-CHz CH:91-03 OCH: 1150601110 COOH HsQflCHzO CO0H III I\' 0 out ECHOCHOHCHzNHJfCHaRe l RI KBH, NHQC(CH3)R;CH2R2 HsC CHzO COOH HsCeCHgO COOHout no c moncmml donut: d'HcHiNH 0 out) mount.

H5C5CH10- COQCH: H5C5CH1O CHnOI].

VII VIII H0 cat (JHCHINHdJCHzRu R1 i CHIOH and subsequent hydrolysis tothe corresponding substituted phenylglyoxal product, XIII. Reductiveamination of XII or XIII with LiAll-I yields S-hydroxy-a- (substitutedaminomethyl)m-xylene'a-a'diol (IX). Alternatively, reductive aminationof XII or XIII-with KBl-I, and the appropriate amine gives esterintermediate XIV. Reduction of XIV with LiAll-I gives IX.

hydroxyisophthalate,'171 g (1 mole) of benzylbromide and 138 g (1 mole)of K CO in 1 l. of acetone was refluxed for 18 hours. The reactionmixture was evaporated to a residue which was extracted with hotcyclohexane to give the crystalline product in a quantitative yield uponcooling. The analytical sample was obtained by recrystallization fromcyclohexane, mp. 94-95.

C O OCH: O OCH:

DMS O H NaH IIO COOCHa lIO- -%3CH@SCH1 X XI CH: C O OCH; 0 O OCH:CIIOHCHgNHCCI-IQRE OCH: LiAlHi II HO fi-Cg HO ("L-CHO NH2C (CH3) R CH1R2IIO CHaOlI 0 S OH:

XII XIII IX KBH ,NH2C (CHJ)R1GH21{2 LIAII'I; ([JHOHCHzNHCWHURiCHaR:

HO- O 0 OCH:

XIV

The compounds of this invention have bronchodilator (B-sympathomimetic)activity useful in the treatment of bronchial asthma and relatedbronchial spasms. In animals such as dogs, a dose of about 0.1-5 mg/kg(i.p.) is effective to prevent an increase in pulmonary resistance dueto bronchial spasms induced by the aerosol administration of 1 mg ofhistamine. Minimal car- EXAMPLE 2 Methyl5-benzyloxyhydrogenisophthalate., A mixture of 91.0 g (0.304 mole) ofdimethyl 5-benzyoxisophthalate and 13.4 g (0.334 moles) of NaOH in diacstimulant or heart rate increases are observed at 500 ml of MeOH wasrefluxed for 2.5 hrs. The mixture this dosage level. The compoundsexhibit the same potency in the guinea pig against aerosolizedhistamine. Further, these compounds selectively exert their therapeuticeffect in the lung following either oral or parenteral administration.

The compounds of this invention are indicated in the treatment ormanagement of bronchial asthma. The dose required is within theabove-described dosage range which, of course, can be varied dependingupon the severity of the condition being treated and the age and sex ofthe patient, by methods well known to the clinical arts.

In order to use these compounds theyare combined with diluents such aslactose, dicalcium phosphate and compounded into dosage forms such astablets by methods well known to the pharmacists art. They can also beformulated as an aerosol by suspending the selected compound in avehicle such as normal saline and formulated by standard pharmaceuticalprocedures.

In order to enhance and broaden the therapeutic spectrum of thesecompounds other therapeutic agents such as steroids, typically thosederived from the cortisone series, may also be included in these dosageforms.

In order to further illustrate the practice of this invention, thefollowing examples are included:

EXAMPLE 1 Dimethyl S-benzyloxyisophthalate. A mixture of 156 g (0.743mole) of dimethyl 5- was evaporated to a residual solid which wasdissolved in EtOAc (l 1.) and washed with H O (2X500 ml). The aqueousphase was acidified with HCl and re-extracted with EtOAc (3X500 ml).After drying the EtOAc extract of acid phase with MgSO evaporation ofthe EtOAc gave a crude White solid which was recrystallized from MeOH-HO to give 70.1 g (80.5%) mp. l47-150. The analytical sample was obtainedby recrystallization from MeOH-H O, mp. l54l55.

Anal. Calcd. for C H O C, 67.13, H, 4.93. Found: C, 67.02; H, 4.99.

EXAMPLE 3 3-Benzyloxy-5-carboxy-a-(methylsulfinyl)- acetophenone.

To a mixture of DMSO (210 ml) and benzene (420 ml) heated with NaI-I, 57percent in oil (13.0 g, 0.31 mole) for 1 hr. at 75 a DMSO solution (270ml) containing 27.0 g (94.7 mmoles) of methyl5-benzyloxyhydrogenisophthalate was added. The mixture was stirred atroom temperature for 2 hrs. and then added to 3 l.

i of Et O. The Na salt was collected and dissolved in H 0 (200 ml) whichwas then acidified to pH5 with HOAc. Cooling gave a yellow precipitate;yield 29.9 g (95.2%) mp. l28-134. Recrystallizations from 2-PrOI-I/hexane gave the analytical material, mp. l37-l40 dec.

Anal. Calcd. for C I-1, 0 5: C, 61.43; H, 4.85; S, 9.65. Found: C,61.13; H, 4.86; S, 9.57.

EXAMPLE 4 3-Benzyloxy-5-carboxyphenylglyoxal and 3-benzyloxy-S-carboxyphenylglyoxal methylthio-methyl acetal. A mixture of40.0 g (120 mmoles) of 3-benzyloxy-5-carboxy-a-(methylsulfinyl)acetophenone, 1.6 1. of 50 percent aqueousHOAc and 0.8 1. MeOH was refluxed for 68 hrs. The mixture was extractedwith CHCl 1X3 1.). The CHCl phase was dried with MgSO, and evaporated togive a quantitative yield of a light yellow solid, mp. l65168 which waspurified by recrystallization from benzene-hexane, mp. 167-169 dec.

EXAMPLE 5 3-Benzyloxy-5-[2-(isopropylamino)- l -hydroxye thyl]-benzoicacid. The 3-benzyloxy-5-carboxyphenylglyoxal (120 moles) was dissolvedin MeOH (l l.) and cooled to lsopropylamine (200 ml) was added at 0 andthe resulting mixture was stirred at 0 for 1 hr. before KBH, (12.2 g,228 moles) was added over a period of 2 hrs., portionwise. The resultantmixture was allowed to stir at room temperature overnight before it wasevaporated to a residual glass. The residue was acidified with 6N HCl (11.) and extracted with CHCl (l 1.). The solid HCl precipitated from theCHCl extract upon standing; yield 21.9 g which gave 20.0 g (50 percent)mp. 290-292 dec. of the free base upon stirring in aqueous NH OH andcollecting by filtration.

Anal. Calcd. for C I-l NO C, 69.28; H, 7.04; N, 4.05. Found C, 68.74; H,7.07, N, 4.01.

EXAMPLE 6 Methyl 3-benzyloxy-5-[2(isopropylamino)-lhydroxyethyl]-benzoate. A mixture of 19.0 g (57.8mmoles) of3-benzyloxy-5-[2- (isopropylamino)l-hydroxyethyl]-benzoic acid and 7.7 g(70.0mmoles) of ethanesulfonic acid was refluxed for 20 hrs. The mixturewas then evaporated in vacuo and the residue obtained was dissolved inCHCl (500 ml). After washing the CHCl solution with percent NaH- CO l250 ml) and drying with MgSO the crude ester was obtained by evaporationof the CHCl yield 17.5 g (88.3%). The analytical sample was obtained asthe HCl salt from Z-PrOH/Et O, mp. 164-165.

Anal. Calcd. for C H NO 'HCl: C, 63.24; H, 6.90; N, 3.69; Cl, 9.33.Found: C, 63.07; H, 6.99; N, 3.89; Cl, 9.15.

EXAMPLE 7 5-Benzyloxy-a-[ (isopropylamino )methyl l-m-xylenea,a'-diol.To a suspension of LiAlH, (4.57 g, 120 moles) in anhydrous Et O (0.5 1.)was added an ethereal solution (0.5 l.) of the methyl3-benzyloxy-5-[2-(isopropylamino)- l-hydroxyethyl1-benzoate (17.5 g,50.9mmoles) slowly at room temperature. The resultant mixture was heatedat reflux for 4 hrs. The LiAlH, and complex was hydrolyzed by the slowaddition of 40 ml of H 0. The granular precipitate which formed wasremoved by filtration and an oily product was obtained from the eitherfiltrate after evaporation; yield 15.2 g. (94.3%). The crude product wascrystallized from Et O-hexane; yield 9.24 g (57.4%) mp. 84-89. Theanalytical sample was obtained from EtOAc-hexane, mp. 9093.

Anal. Calcd. for C H NO C, 72.35; H, 7.99; N, 4.44. Found C, 72.21; H,8.17; N, 4.18.

EXAMPLE 8 5-Hydroxy-a-[(isopropylamino)methyl]-m-xylenea,a'-diolhemifumarate. An ethanol solution (200 ml) containing 9.34 g(29.6mmoles) of crystalline S-benzyloxy-a-[(isopropylamino)methyl]-m-xylene-a,oz'-diol was hydrogenated over 4.0 gof 10 percent Pd-C catalyst until hydrogen uptake had ceased (1 hr.).The catalyst was removed by filtration through a celite pad and thefiltrate was evaporated to give an oily residual product. A crystallinefumarate salt was obtained; yield 6.71 g (8.20%) mp. 230245 dec. Theanalytical sample was obtained from MeOH-Et O; yield 6.13 g (73.2%) mp.246-248 dec.

Anal. Calcd. for C H NO l/2C.,H,O C, 59.35; H, 7.47; N, 4.94. Found: C,59.28; H, 7.45; N, 4.80.

EXAMPLE 9 3 -Benzyloxy-5 -[2-(tert-butylamino)-1-hydroxyethyl]-benzoicacid. A solution of 3-benzyloxy-5-carboxyphenylglyoxal (l20mmoles) inMeOH (1 l.) was stirred at 0 for 1 hr. KBH (12.2 g, 228mmoles) was addedat 0 in aliquots over a period of 3 hrs. and the resulting mixture wasstirred at room temperature overnight. The mixture was evaporated invacuo and the residue obtained was acidified with 3N HCl (400 ml). Theaqueous mixture was extracted with CHCl (3X500 ml). The CHCl extractswere combined and ether was added after cooling. A white precipitate wascollected; yield 23.6 g (51.8%) mp. 222-225 dec of the product HCl salt.The analytical sample was obtained from 2- PrOH/Et- O, mp. 228-230 dec.The free base was obtained by stirring the salt in NH OH. Filtrationgave 15.2 g (36.9%) mp. 270-272 dec.

Anal. Calcd. for C H NO HCl: C, 63.24; H, 6.90; N, 3.69; Cl, 9.33.Found: C, 63.02; H, 7.04; N, 3.45; Cl, 9.36.

EXAMPLE 10 Methyl 3-benzyloxy-5-[2-(t-butylamino)-1-hydroxyethyl]-benzoate. A mixture of 15.2 g (44.3mmoles) of3-benzyloxy-5-[2- (t-butylamino)-l-hydroxyethyl]-benzoic acid and 5.5 g(SOmmoles) of ethanesulfonic acid was heated at reflux for 20 hrs. in300 ml of MeOH. The reaction mixture was evaporated in vacuo to give acrude oily residue which was partitioned between CHCl (500 ml) and 5%NaHCO (200 ml). The CHCl phase was dried with MgSQ, and evaporated togive a solid residue in a quantitative yield. A crystalline HCl salt wasobtained from Z-PrOH/Et O, mp. l92-l95.

EXAMPLE 1 l 5-Benzyloxy-a-[(t-butylamino)methyl]-m-xylenea,a-diolfumarate.

To a suspension of LiAlH, (3.42 g, mmoles) in 300 ml of dry THF wasadded a THF solution (500 ml) of the methyl 3-benzyloxy-5-[ 2(t-butylamino l hydroxyethyl1benzoate (14.8 g, 41.3 mmoles). The reactionmixture was refluxed for 4 hrs. The LiAlH, and complex was hydrolyzed bythe addition of 40 ml of H 0, slowly. The granular precipitate whichformed was removed by filtration and the THF filtrate was evaporated togive 13.1 g (95.3%) of crude product as an oil. A crystalline fumaratesalt was obtained from MeOH-Et O; yield 10.7 g (66.8%) mp. 195200 dec.Anal. Calcd. for C20H27N03-l/2 (L l I404: C, H, 7.54; N, 3.61. Found: C,67.79; H, 7.68; N, 3.40.

EXAMPLE l2 a-[(t-butylamino)methyl]-5-hydroxy-m-xylene-a,a'- diolhemifumarate. An ethanolic solution (200 ml) containingS-benzyloxy-a-[(t-butylamino) methyl]-mxylene-a,a'-diol EXAMPLE 15 (8.25g, 25.1mmoles) was hydrogenated over 4.0 g of 10 y 'p y y 1' 10% Pd-Ccatalyst until hydrogen uptake had ceased (1 hr.). The catalyst wasremoved by filtration through a celite pad and the EtOl-l filtrate wasevaporated to give an oily residual product; yield 5.75 g (95.9%). Acrystalline hemifumarate salt was obtained from MeOH- Et O; yield 5.06 g(67.9%) mp. 24925 1 dec. The analytical sample was obtained byrecrystallization from MeOH-Et O; yield 3.33 g (44.7%) mp. 263-265 dec.Anal. Calcd. for C H NO 'l/2C H O C, 60.59; H, 7.80; N, 4.71. Found: C,60.79; H, 7.88; N, 4.56.

EXAMPLE 13 Methyl 3-benzyloxy-5-[2-(1,l dimethyl-2- phenylethylamino 1-hydroxyethyl -benzo ate.

The 3-benzyloxy-S-carboxyphenylglyoxal 120 mmoles) was dissolved in MeOH(1 1.) and cooled to' l,1-Dimethyl-2-phenylethylamine (100 g, 0.67moles) was added at 0 and the resulting mixture was stirred at 0 for 1hr. before addition of KBH, (12.2 g, 228 mmoles) over a period of 2 hrs.portionwise. The resultant mixture was allowed to react at roomtemperature for 18 hours before it was evaporated to.a residual glass.The residue was acidified with 6N l-lCl (1 l.) and extracted with CHCl;,(1 1.). Addition of ether to the CHCl extract gave the l,1-dimethyl-2'phenylethylamine HCl as a white precipitate which was removed byfiltration. The CHCl filtrate was evaporated to give the crude3-benzyloxy-5-[2-(1,1dimethyl-2-pheny1ethylamino)-1-hydroxyethyl]benzoic acid HCl. The base wasobtained by treating the crude salt with conc. NH OH, extracting withCHCl and drying with MgSO before evaporation to give the crude oilybase.

A mixture of 3-benzyloxy-5-[2-(1,1-dimethyl-2-phenylethyl)-2-hydroxyethyl]-benzoic acid (120 mmoles) and 17.7 g (160mmoles) of ethanesulfonic acid was heated at reflux for 18 hours in 500ml of MeOH. The reaction mixture was evaporated to a residual oil whichwas dissolved in Cl-lCl (200 ml) and washed with 5% Nal-lCO (2X200 ml).The CHCl phase was dried (MgSO and evaporated to give the crude, oilymethyl 3-benzyloxy-5-[(1,1-dimethyl-2-phenylethylamino)-2-hydroxyethyl]-benzoate which was converted to acrystalline hemifumarate salt; yield 14.7 g. (24.8%) mp. 173175 dec.

Anal. Calcd. f0! C27H31NO4'l/2C4H404: C, H, 6.77;, N, 2.85. Found: C,70.90; H, 6.89; N, 2.73.

EXAMPLE 14 hydroxy-m-xylene-a,a'-diol hemifumarate.

An ethanolic solution (200 ml) of the benzyloxy intermediate 8.73 g(21.4mmoles) was hydrogenated over 4.0 g of Pd-C catalyst until hydrogenuptake had 15 ceased (1 hr.). The mixture was filtered through celiteand the filtrate was evaporated and gave an quantitative yield of thefree base product as a clear oil. A white cyrstalline hemifumarate saltwas obtained; yield 6.62 g (82.3%) mp. 209-212 dec. The analyticalsample was obtained by recrystallization from MeOH-Et O;

yield 5.69 g (70.8%) mp. 214215.5 dec.

Anal. Calcd. for C H NO -1/2C H O C, 67.54; H, 7.29; N, 3.75. Found: C,67.45; H, 7.53; N, 3.67.

25 EXAMPLE l6 Methyl benzoate. To a cold suspension of NaH (105 mmole)in 71 ml of DMSO and 71 ml of benzene was added slowly 10.0 g

(47.6 mmoles) of dimethyl S-hydroxyisophthalate dissolved in 25 ml ofDMSO and 25 ml of benzene. The resulting mixture was then heated atreflux for 1.5 hrs; cooled and acidified with 100 ml of 40 percent HOAc.The aqueous phase was separated and extracted with CHC13 (3X250 ml). Thecombined organics were dried (MgSO and distilled off under vacuum givinga gummy residue. The crude gum was washed with hexane (2X20 m1) andtriturated with EtOAc (10 ml) with heat. Cooling gave 4.20 g (35%) of ayellow solid, mp.

144-150. Recrystallizations from EtOAc-hexane gave the analyticalsample, mp. 153l55.

Anal. Calcd. for C I-1, 0 5: C, 51.55; H, 4.72;, S, 12.51. Found: C,51.84; H, 4.90; S, 12.64.

EXAMPLE 17 components gave the crude 3-carboxymthy1-5-hydroxyphenylglyoxal in a quantitative yield.

A methanolic'solution (100 ml) containing the crude substitutedphenylglyoxal was cooled to 0 and 20 ml of t-butylamine was added. Afterstirring the mixture at 0 for 1 hr., KBl-l 1.78 g, 33 mmoles) was addedin 4 aliquots over a 2 hr. period. The mixture was allowed to reach roomtemperature and stir overnight.

The reaction mixture was evaporated in vacuo and the residue obtainedwas suspended in 6N HC] (100 m1) and washed with CHCl (2X50 ml). Theacidic phase was basified with NH OH and extracted with EtOAc (3x200ml). The EtOAc extracts were dried (MgSO and evaporated to give thecrude product as an oil; yield 1.35 g (31%). The product was purified asa hemifumarate salt from MeOH/Et O, mp. 261-262.5 dec.

Anal Calcd. C H NO 'l/2C H O C, 59.07; H, 7.13; N, 4.31. Found: C,59.16; H, 7.19; N, 4.17.

EXAMPLE 18 To illustrate the in vivo effects, compounds wherein R ismethyl and R is hydrogen; R is methyl and R is phenyl; and R and R arehydrogen are tested in dogs which are challenged by the aerosoladministration of 1 mg of histamine. These compounds are identified asW9803A, W989OA, and 9640A respectively in the following table:

on. RFCHPJJNHCHICH -o cm Ha OH wherein R is COOH or COOCH and wherein Ris phenyl or hydrogen, with the proviso that R is hydrogen only when R,is COOH and R is phenyl only when R, is COOCH benzoic acid.

2. A compound according to claim 1 which is 3-benzyloxy-S-[2-(tert-butylamino)-1-hydroxyethyl]- Note: Doses chosen forsalbutanol and Thl 165a still demonstrated a dose-response relationshipand were not on the upper right flat portion of the dose-responsivecurve for the dilation vs, dose. A Hr./Min. change in heart rate perminute.

While salbutamol and Th1165a are more potent bronchodilators than thecompounds of this invention, these known compounds also exhibit theundesirable cardiac stimulatory effects. Consequently, the compounds ofthis invention possess unique therapeutic properties over these knownbronchodilators in that they do not produce significant heartstimulatory actions.

Reference compound structures:

(FHOHCHQNHCHCHS CHOHCHaNHC(CH;)3 IHe H O OH CHzOH l HO HO salbutainelThllfifia We claim:

1. A compound of the formula:

VIII

wherein R and R are hydrogen. 5. A compound of the formula:

CHaOH I I Page l of 2 UNITED STATES PATENT OFFICE CERTIFICATE OFCORRECTION Patent No. 3"'879 44 2 Dated April 22 1225 vlnventofls)Charles F, Schwender,et al It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

. 0n the cover sheet item (54) should read -5-Hyd roxya (SubstitutedAminomethyl)Meta-Xylenea;

Diols Column 9, in the Table, "salbutanol" should read salbutamol Column4-, and claim 4, the formulas should read as shown on the-attachedsheet.

- Page 2 of 2 e Patent No. -5,879, +2

Column CHOHCH NHQCMR R1 7 LiA).H

Q NH2C(CH3)R4CH2R2 HO (ll-[ 0,

Claim 4 A Conmmmd of the formula 2 wzwuctcua-micn scacn io" c ow G vnu Qv l v Signed andifi'caled this I Twenty-fourth Day f n 1916" sum I I IArrest:

c. MARSHALL mum v Commissioner oj'larems and Trademarks 'aq m 'c. MASONAnestr'ng Officer UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTIONPatent No. 5879Lm2 Dated April 1975 O lnventofls) Charles F. Schwenderet al.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 9, in the Table, "salbutanol" should read salbutamol Claim 1,delete "benzoic acid" Claim 2, after "hydroxyethyl]-" insert benzoicacid.

' Signed and flcalcd this second Day of Dawn [SEAL] Attest:

RUTH C. MASON C. MARSHALL DAMN A nesting Officer Commissioner oflntenlsand Trademarks FORM PO-1050 (10- USCOMM-DC 60376-1 69 U.S. GOVERNMENTPRINTING OFFICE: 869. 93 o

1. A COMPOUND OF THE FORMULA:
 1. A compound of the formula:
 2. Acompound according to claim 1 which is3-benzyloxy-5-(2-(tert-butylamino)-1-hydroxyethyl)-benzoic acid.
 3. Acompound according to claim 1 which is methyl3-benzyloxy-5-(2-(1,1-dimethyl-2-phenylethylamino)-1-hydroxyethyl)-benzoate.4. A compound of the formula: